Bilirubin Induced Encephalopathy.

Hyperbilirubinemia is one of the most common neonatal disorders. Delayed diagnosis and treatment of the pathologic and progressive indirect hyperbilirubinemia lead to neurological deficits, defined as bilirubin induced encephalopathy (BIE) (2). The incidence of this disorder in underdeveloped countries is much more than developed areas. All neonates with the risk factors for increased the blood level of indirect bilirubin are at risk for BIE, especially preterm neonates which are prone to low bilirubin kernicterus . BIE can be transient and acute (with early, intermediate and advanced phases)or be permanent, chronic and lifelong ( with tetrad of symptoms including visual (upward gaze palsy), auditory (sensory neural hearing loss), dental dysplasia abnormalities, and extrapyramidal disturbances (choreoathetosis cerebral palsy).Beside the abnormal neurologic manifestations of the jaundiced neonates ,brain MRI is the best imaging modality for the confirmation of the diagnosis. Although early treatment of extreme hyperbilirubinemia by phototherapy and exchange transfusion can prevent the BIE, unfortunately the chronic bilirubin encephalopathy does not have definitive treatment.

time of treatment modalities (phototherapy and exchange transfusion), the adverse effects of hyperbilirubinemia and brain cellular damage can be transient and minimal or permanent and severe.
The symptoms of this disorders can be divided into acute or chronic phases (4).
Although the incidence of jaundice is high in the neonatal population, the rate of severe hyperbilirubinemia leading to chronic bilirubin encephalopathy is low and kernicterus is relatively an uncommon disorder in the developed countries, however, in underdeveloped areas of the world, its occurrences are relatively more common (5). High values of indirect free bilirubin in the blood which couldn't bound to albumin can transfer from the blood-brain barrier and precipitate in the brain cells and disturb the normal functions of central nervous systems (6). Regarding of the Rh incompatibility between the mother and neonate as the most common cause of severe hyperbilirubinemia, and the introduction of RhoGam(anti Rh antibody) since the beginning of 1960, maternal sensitivity to fetal antigens, during pregnancy and after delivery is declined and recently ABO incompatibility is the most important cause of neonatal jaundice (7).
Given that the severity of hyperbilirubinemia in ABO incompatibility is less than Rh

Incidence
Despite the understanding of the basic pathophysiology of bilirubin toxicity and available treatment modalities of this disorder, unfortunately, bilirubin encephalopathy is reported all over the world, however, the new cases of the disease in underdeveloped countries is much more than 9

Bilirubin Induced Encephalopathy
Iran J Child Neurol. winter 2020 Vol. 14 No. 1 the developed ones. We did not have the definite incidence of disease in our country Iran, but the incidence range of kernicterus in developed countries is reported 1 in 40000 live birth (10). In a recent report of Sweden, while the incidence of extreme hyperbilirubinemia needs to exchange transfusion is 50 in 100000 live births, fortunately, the incidence of kernicterus is reported 1.3 in 100000 live births (11). Regarding of the occurrence of low bilirubin kernicterus in preterm infants and overlap of the symptoms of bilirubin toxicity with the other neurological sequelae of prematurity, the exact incidence of BIE in premature neonates is not specified. In a recent study in japan in preterm neonates with gestational age lower than 30 weeks, the incidence of kernicterus reported 1.8 in 1000 live birth (12).

Pathophysiology
Deposition of indirect and unconjugated bilirubin in the brain cells is the main underlying pathophysiologic process of BIE (13).
Globus pallidus, basal ganglia, substantia nigra, hippocampus, thalamic nuclei, putamen nuclei, dentate, inferior olives, and cerebellum are the most vulnerable areas of the brain to the toxicity induced by bilirubin with a symmetric pattern of involvement in the mentioned areas. The cranial nerves, primarily the third, fourth, and sixth ones also involved in this disorder (14). Cochlear Deposition of indirect and unconjugated bilirubin in the brain cells is the main underlying pathophysiologic process of BIE (13).
Globus pallidus, basal ganglia, substantia nigra, hippocampus, thalamic nuclei, putamen nuclei, dentate, inferior olives, and cerebellum are the most vulnerable areas of the brain to the toxicity induced by bilirubin with a symmetric pattern of involvement in the mentioned areas. The cranial nerves, primarily the third, fourth, and sixth ones also involved in this disorder (14). Cochlear nuclei, oculomotor and vestibular system involve too. Associated destructive lesions in the white matter and periventricular infarcts have been reported. The cerebral cortex is spared (15) Intense yellow coloring of the mentioned areas of the brain in autopsy revealed deposition of indirect bilirubin in these sites. (Figure-1) In the evaluation of cellular pathology, impairment of the glucose transport system, DNA, protein and neurotransmitter synthesis and activity of many enzymes, iron transport and apoptosis are detected. Degeneration of mitochondria, and membrane alterations of brain cells, cause the irreversible and permanent changes leading to chronic bilirubin encephalopathy (16).

Risk factors for bilirubin induced encephalopathy
Although in all neonatal populations, delay diagnosis and treatment of severe hyperbilirubinemia is the main cause of bilirubin encephalopathy, there are many risk factors for the pathologic raising the blood level of indirect bilirubin in CNS.
Considering that this disorder, has a multifactorial etiologist, there are other risk factors than bilirubin level, increase the probability of this disease. All underlying disorders for increasing the blood levels of bilirubin such as hemolytic disease of newborns, sepsis, neonatal nonimmune hemolytic disorders such as congenital spherocytosis, G6PD deficiency, congenital and genetic-based disorders for bilirubin metabolism such as Crigler-Najjar and Lucey-Driscoll syndromes, hypoalbuminemia, acidosis, hypoglycemia are known predisposing factors for bilirubin toxicity (1,17).
Regard to the immaturity of the blood-brain barrier (BBB) in the neonatal period and necessitate of the passage of indirect bilirubin from the BBB, for deposition of bilirubin in the brain cell, all disorders with the damage of the BBB or increase its permeability to bilirubin, can be a major risk factor for bilirubin toxicity. Hypoxic-ischemic encephalopathy, prematurity, sepsis, and meningitis are the main underlying disorders with effect by this mechanism (18). Other risk factors consisted of low birth weight, cephalhematoma or easy bruising, exclusive or unsuccessful breastfeeding, early discharge from the nursery (lower than 24-48 hours of life), lack of predischarge screening of hyperbilirubinemia of neonates (19) .
New research focus on the Genetic tendency for BIE. Determination of the underlying genetic tendency, help the healthcare services to select the patient susceptible to BIE for more aggressive management of neonatal jaundice compared to other patients without this genetic tendency (20).

Low bilirubin Kernicterus
The occurrence of BIE by the bilirubin level lower than the expected plasma level need to exchange transfusion or high intensive phototherapy is, Although these deficits have modest intensity, more research is needed for confirmation of the exact correlation between these late sequelae of neonatal hyperbilirubinemia (24).

Clinical manifestations Transient bilirubin encephalopathy
In some newborns with high levels of bilirubin, early bilirubin toxicity is reversible and transient. There In this situation, neonates exposed to bilirubin levels of lesser severity than in classic kernicterus.

Acute bilirubin encephalopathy (ABE)
The acute symptoms of disease divided into 3 phases which are listed below: Early phase: In the first 3-5 days of the disease, the nonspecific symptoms of slight lethargy, poor feeding, poor sucking, slight hypotonia and hyperreflexia, slightly high pitch cry are seen.

Chronic bilirubin encephalopathy
In the first year of life hypotonia, hyperreflexia, delayed motor skill, persistent tonic neck reflex, and retardation of neurodevelopmental milestones are present. Extrapyramidal movements well developed after several years. During the late infancy and childhood, a tetrad of symptoms including visual (upward gaze palsy), auditory (sensory neural hearing loss), dental dysplasia abnormalities, and extrapyramidal disturbances (choreoathetosis cerebral palsy) are presented in the patients. (29) Intellect is relatively spared. Auditory dysfunction: Auditory brainstem center is the first and the most affected structure in the patient by BIE. After that, the auditory nerve is involved but, the cochlea and hair cells spared. (30) Then the hearing loss due to  (29). Intellect is relatively spared.
Auditory dysfunction: Auditory brainstem center is the first and the most affected structure in the patient by BIE. After that, the auditory nerve is involved but, the cochlea and hair cells spared (30). Then the hearing loss due to bilirubin encephalopathy is central (brain stem) and in a lesser extent has a peripheral origin. Sensorineural hearing loss may be the only symptom of bilirubin encephalopathy.
In most cases, the auditory disturbance is a highfrequency loss, and usually is bilateral. Treatment of hyperbilirubinemia led to a considerable decrease in the incidence of hearing loss.
Auditory neuropathy or auditory dyssynchrony is one of the other hearing problems with bilirubin toxicity which differs from typical hearing loss.
In this situation, there is little or no hearing loss, but abnormal processing of sound is seen. Sound localization and speech discrimination is the product of this disorder.       Regard to the normal intelligent quotient (IQ) in most of the patients with kernicterus, auditory and motor dysfunction of the patient must not mistake with severe cognitive impairment